Klotho: Therapeutic Agent for Ischemia Reperfusion Induced Acute Kidney Injury

Klotho：缺血再灌注引起的急性肾损伤的治疗剂

• 批准号: 8335457
• 负责人: Ming-Chang Hu
• 金额: $ 34.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335457
• 关键词: Ablation; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; American; Animals; Apoptosis; Attenuated; Biological Markers; Body Fluids; Brain; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Research; Complex; Critical Illness; Cytoprotection; Data; Databases; Dependence; Development; Diagnosis; Diagnostic; Dialysis procedure; Dose; Epithelial Cells; Erythropoiesis; Erythropoietin; Fibrosis; Functional disorder; Genes; Healed; Heart; Heart Injuries; Hospitals; Hypoxia; Hypoxia Inducible Factor; Hypoxic Brain Damage; In Vitro; Incidence; Inflammation; Injury; Investigational Therapies; Ischemia; Kidney; Knock-in Mouse; Knockout Mice; Metabolic; Modality; Modeling; Mus; Natural regeneration; Outcome; Oxidative Stress; Pathway interactions; Patients; Play; Population; Prevalence; Process; Proteins; RNA Interference; Rattus; Recording of previous events; Recovery; Reperfusion Injury; Reperfusion Therapy; Resistance; Rodent Model; Role; Simulate; Staging; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Translating; Tubular formation; Uncertainty; Work; aging gene; anti aging; base; clinical practice; efficacy testing; fibrogenesis; functional loss; healing; hypoxia inducible factor 1; in vivo; insight; interest; kidney cell; klotho protein; mortality; mutant; novel; novel strategies; outcome forecast; overexpression; oxygen transport; pre-clinical; prevent; protective effect; receptor; receptor expression; renal ischemia; repaired; research clinical testing; research study; response; senescence; success; tissue regeneration; transcription factor; tubular necrosis

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a critical clinical problem. The annual prevalence of AKI is 22-620 per million populations in the USA. In particular, the AKI incidence is extremely high in critically ill patients with high mortality. Current overall mortality is still unacceptably high at ~ 30%. Even if patients survive the acute insult, long-term prognosis after AKI is still far from optimal. Of surviving patients, 5-20% are still dialysis-dependent at hospital discharge. The prevalence chronic kidney disease (CKD) is currently estimated at 26 million (16.5%) Americans. Of note, a significant number of CKD patients have a history of AKI. Furthermore, patients with pre-existing CKD are more susceptible to renal insults and have a poorer outcome and higher mortality when they develop AKI. Thus, efficient treatment of AKI is an effective modality to block the development of CKD. Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that regulate(s) many genes involved in angiogenic, metabolic, and oxygen transport functions. HIF1/2 activation protects the kidney from IRI. Erythropoietin (EPO) has also been used for treatment of ischemic injury in the brain, heart, and kidney. Mice null for either EPO or EpoR have delayed tissue regeneration post ischemia, which suggests that EPO-EpoR is protective against hypoxic brain injury and heart injury. But the EpoR effect on AKI is relatively poorly documented. Moreover, the relationship of Klotho to HIF(s) and EpoR in the kidney is not defined. To date, renal replacement remains the sole treatment for AKI and improvement in outcome has been modest. Dialysis, though effective in maintaining body fluid composition and volume, is not able to ameliorate kidney damage and promote kidney regeneration. We found that Klotho is not only an early biomarker for AKI patients, but also confers renoprotection to attenuate kidney injury, and potentially promote recovery and prevent CKD development. Klotho protein may turn out to be a most promising protein for clinical AKI, but a lot of work still needs to be done. In this proposal, we propose a hypothesis that encompasses the existing database including our own preliminary data; and put it to test. Doubtlessly, this therapeutic study will provide more interesting and encouraging results to inspire to use Klotho protein as a novel strategy. We will also explore whether the mechanism of renoprotection by Klotho is through HIF(s) and EpoR. This data will set the stage for therapeutics as we are at an advanced stage of preclinical experimentation, placing us at a very close proximity to clinical testing.

描述（由申请人提供）：急性肾脏损伤（AKI）是一个关键的临床问题。在美国，AKI的年度患病率为每百万人群22-620。特别是，死亡率高的重症患者的AKI发病率极高。目前的总死亡率仍然不可接受，约为30％。即使患者在急性侮辱中幸存下来，AKI后的长期预后仍然远非最佳。在存活的患者中，有5-20％的患者仍然依赖于医院出院。患病率慢性肾脏病（CKD）目前估计为2600万（16.5％）。值得注意的是，大量的CKD患者有AKI病史。此外，现有CKD的患者更容易受到肾脏损害的影响，并且在出现AKI时的结果较差和更高的死亡率。因此，对AKI的有效处理是阻止CKD发展的有效方式。低氧诱导因子（HIF）是一个异二聚体转录因子，该因子调节了许多与血管生成，代谢和氧运输功能有关的基因。 HIF1/2激活可保护肾脏免受IRI的侵害。红细胞生成素（EPO）也已用于治疗大脑，心脏和肾脏缺血性损伤。缺血后的EPO或EPOR无效的EPO或EPOR的无效组织再生延迟，这表明EPO-EPOR可防止缺氧性脑损伤和心脏损伤。但是EPOR对AKI的影响相对较差。此外，尚未定义Klotho与HIF（S）和Epor的关系。迄今为止，肾脏替代仍然是AKI的唯一治疗方法，并且结果的改善是适度的。透析虽然有效地维持体液组成和体积，但无法改善肾脏损伤并促进肾脏再生。我们发现，克洛托不仅是AKI患者的早期生物标志物，而且还赋予了肾脏保护以减轻肾脏损伤，并有可能促进康复和预防CKD的发展。 Klotho蛋白可能是临床AKI的最有希望的蛋白质，但是仍然需要做很多工作。在此提案中，我们提出了一个假设，该假设涵盖了现有数据库，包括我们自己的初步数据；并进行测试。毫无疑问，这项治疗性研究将提供更有趣和令人鼓舞的结果，以激发使用Klotho蛋白作为一种新型策略。我们还将探讨克洛托（Klotho）的重生保护机制是否是通过HIF（S）和EPOR进行的。由于我们处于临床前实验的高级阶段，因此该数据将为治疗剂奠定阶段，使我们处于非常靠近临床测试的近端。